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Wiley Open Access, Molecular Systems Biology, 11(11), p. 838, 2015

DOI: 10.15252/msb.20156458

Wiley Open Access, Molecular Systems Biology, 4(12), p. 866, 2016

DOI: 10.15252/msb.20166982

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Frequency modulation of ERK activation dynamics rewires cell fate

Journal article published in 2015 by Hyunryul Ryu, Minhwan Chung, Maciej Dobrzyński, Sung Sik Lee, Dirk Fey, Yannick Blum, Sung Sik Lee, Matthias Peter ORCID, Boris N. Kholodenko, Noo Li Jeon, Noo Li Jeon, Olivier Pertz
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Transient versus sustained ERK MAP kinase (MAPK) activation dynamics induce proliferation versus differentiation in response to epidermal (EGF) or nerve (NGF) growth factors in PC-12 cells. Duration of ERK activation has therefore been proposed to specify cell fate decisions. Using a biosensor to measure ERK activation dynamics in single living cells reveals that sustained EGF/NGF application leads to a heterogeneous mix of transient and sustained ERK activation dynamics in distinct cells of the population, different than the population average. EGF biases toward transient, while NGF biases toward sustained ERK activation responses. In contrast, pulsed growth factor application can repeatedly and homogeneously trigger ERK activity transients across the cell population. These datasets enable mathematical modeling to reveal salient features inherent to the MAPK network. Ultimately, this predicts pulsed growth factor stimulation regimes that can bypass the typical feedback activation to rewire the system toward cell differentiation irrespective of growth factor identity.